FY2012 has seen significant progress toward accomplishing all of the Specific Aims. For Aim 1, a major effort in the TNU has been to image small parenchymal veins. We have demonstrated that images acquired at clinical field strength (3T) are sufficiently detailed not only to identify small parenchymal veins but also to characterize them, and we can now reliably demonstrate the presence of central veins within most white matter MS lesions. We have also demonstrated similar findings in lesions in an experimental autoimmune encephalomyelitis (EAE) model induced in the marmoset monkey. In order to optimize the detection and analysis of perivenular lesions for clinical research, and to translate this new method into clinical practice, we have introduced a new type of MR image, which we have called FLAIR*. We have used this technique to demonstrate that intralesional MS veins are smaller than uninvolved control veins, perhaps compressed by perivascular inflammatory cells or by fibrosis of the vascular wall. We have also found that extralesional MS veins appear larger than their counterparts in non-MS cases. By investigating developing MS lesions at high resolution using a 7T scanner, we have confirmed and extended earlier work demonstrating that opening of the blood-brain barrier in new MS lesions is a dynamic process that changes over time as lesions grow and begin to repair. Our observations have led to a reinterpretation of blood-brain-barrier opening in terms of a competition between tissue damage, which at least initially proceeds outward from the central vein, and tissue repair (or the prevention of damage), which is most intense at the periphery. For Aim 2, in collaboration with the Advanced MRI Section (PI: Jeff Duyn) in the Laboratory of Functional and Molecular Imaging in NINDS, we have been pursuing a related approach to myelin imaging. This approach, which uses T2* relaxation, offers several advantages over the conventional T2-based approach: It can be applied more readily on high-field MRI systems (3T and above) due to lower power deposition, amplifying both signal and contrast relative to background; data can be obtained much more rapidly through a multi-gradient-echo pulse sequence; and sensitivity to myelin should be increased because myelin itself, due both to its chemistry and to its highly ordered structure in white matter, induces susceptibility changes. We therefore investigated whether T2* decay at 7T can be used to detect and characterize myelin water in both healthy human and marmoset brains. Using a three-compartment model (triple exponential fit), we demonstrated the presence of a short T2* component in white matter fiber bundles in both species. Consistent with previous work at lower field strength, we found that this rapidly relaxing component (T2*6 ms) accounts for 13% of the total MR signal, whereas a more slowly relaxing component (T2*30 ms) accounts for most of the remaining signal (80%). We have further demonstrated that T2* in myelinated tracts running perpendicular to the main magnetic field can change by as much as 50% when the animal is rotated 90. Our goal is to investigate susceptibility effects on the short T2* component directly, with the goal of building a quantitative model to describe more accurately the behavior of the myelin water signal at high field strength. We have also been investigating the imaging correlates of axonal damage using a technique known as diffusion-weighted spectroscopy, which allows measurement of the diffusion properties of intracellular metabolites, particularly the intraneuronal metabolite N-acetylaspartate (NAA). Our initial result using this technique is that diffusion of NAA parallel to the axon is significantly lower in MS cases than in healthy volunteers and is moreover inversely correlated with the diffusion of water in the same direction. This is consistent with biophysical models that suggest that axonal damage should reduce diffusivity and helps to resolve a paradox in the literature. Our results suggest that NAA diffusivity is a more specific marker of white matter integrity than water diffusivity. For Aim 3, we have developed new and fully automated image segmentation techniques to identify the volumes of brain structures, including lesions. We used this technique to demonstrate, in a cross-sectional study, that the total amount of white matter in MS is surprisingly within normal limits. However, the same analysis demonstrates that MS cases with more white matter have less clinical disability. This may be related to more successful tissue repair, perhaps even remyelination, in some individuals, and a longitudinal study is underway to assess this hypothesis. We have also developed an automated longitudinal method, based on subtraction MRI, that can segment, identify, and track individual lesions. This method will allow us to investigate patterns of lesion growth and recovery and to learn how those patterns change over the course of the disease and in response to the initiation of different disease-modifying therapies.